Abstract
MicroRNAs (miRs) are master regulators of post-transcriptional gene expression, and they are often dysregulated in individuals suffering from diabetes. We investigated the roles of miR-101-3p and miR-204-5p, both of which negatively regulate insulin secretion and cell survival and are highly expressed in pancreatic β cells, in the context of type 1 diabetes (T1D) pathogenesis. Using quantitative real time PCR, we evaluated serum levels of miR-101-3p and miR-204-5p in four groups, including recent-onset T1D patients (T1D group; n = 50), individuals with normal glucose levels expressing one islet autoantibody (Ab) (single Ab group; n = 26) or multiple autoantibodies (multiple Ab group; n = 12), and healthy controls (control group; n = 43). An in silico analysis was performed to identify potential target genes of these miRNAs and to delineate enriched pathways. The relative expression of serum miR-101-3p was approximately three times higher in the multiple Ab and T1D groups than that in the single Ab and control groups (p < 0.0001). When considering all groups together, miR-101-3p expression was positively correlated with the level of islet autoantibodies GADA (r = 0.267; p = 0.0027) and IA-2A (r = 0.291; p = 0.001), and the expression of the miRNA was not correlated with levels of ZnT8A (r = 0.125; p = 0.183). miR-101-3p expression did not correlate with HbA1c (r = 0.178; p = 0.052) or glucose levels (r = 0.177; p = 0.051). No significant differences were observed in miR-204-5p expression among the analyzed groups. Computational analysis of the miR-101-3p target gene pathways indicated a potential activation of the HGF/c-Met, Ephrin receptor, and STAT3 signaling pathways. Our study demonstrated that the circulating levels of miR-101-3p are higher in T1D patients and in individuals with normal glucose levels, testing positive for multiple autoantibodies, indicating that miR-101-3p precedes loss of glucose homeostasis. The pathogenic role of miR-101-3p in T1D may involve multiple molecular pathways.
Highlights
The loss of functional pancreatic β-cells is a key factor in the pathogenesis of both type 1 and type 2 diabetes [1, 2]
Circulating hsa-miR-101-3p was upregulated in type 1 diabetes (T1D) patients and non-diabetic individuals positive for two or more islet autoantibodies
Using 1.0-fold change as the cutoff, we found that the number of subjects displaying upregulated serum miR-101-3p was similar between the control (43.9%) and single Ab (22.7%) groups, but lower than those of the multiple Ab (83.3%) and T1D (85.7%) groups (p < 0.0001), conferring odds ratios of 6.39 [confidence interval (CI): 1.24–32.91; p = 0.02] and 7.67 (CI: 2.79–21.06; p < 0.001) for multiple Ab and T1D groups, respectively, relative to control group, and odds ratios of 17 (2.76–104.6) and 20.4 (5.68–73.28), respectively, relative to single Ab group
Summary
The loss of functional pancreatic β-cells is a key factor in the pathogenesis of both type 1 and type 2 diabetes [1, 2]. Type 1 diabetes (T1D) is a heterogeneous autoimmune disease resulting from numerous mechanisms that lead to the destruction of insulin-producing pancreatic islet β cells and chronic hyperglycemia. MiR-204 inhibits insulin transcription by targeting the transcription factor MAFA (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A) [20] It promotes β cell apoptosis induced by endoplasmic reticulum stress through regulation of the unfolded protein response-related protein kinase R-like ER kinase (PERK) [21]. Given the possible relevance of miR-101-5p and miR-204-5p in reducing insulin secretion and β cell death, both of which are paramount events in early T1D pathogenesis, we analyzed their expression in serum samples from four clinical groups that included patients with recent-onset autoimmune diabetes, individuals without diabetes expressing single or multiple islet autoantibodies, and healthy controls. To provide new insights into the roles of the differentially expressed miRNAs in the pathogenesis of T1D, we performed pathway and functional enrichment analyses of putative target genes of the differentially expressed miRNAs
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